Chloroquine Sensitive Plasmodium falciparum for MultiValent Vaccine & Challenge

描述（由申请人提供）：消除恶性疟原虫（Pf）的理想工具，恶性疟原虫是99%疟疾死亡的病原体，是一种高效疫苗， 防止血液阶段感染，从而防止所有疾病和传播。Sanaria的目标是开发和商业化Pf子孢子（SPZ）疫苗，其在> 80%的接受者中预防Pf血液期感染。Sanaria开发了一种由减毒、纯化、无菌、冷冻保存的PfSPZ组成的疫苗，PfSPZ疫苗基于氯喹敏感的NF 54菌株。通过皮内（ID）、皮下（SC）或静脉内（IV）注射给予人类志愿者时，该疫苗安全且耐受性良好（1）。它是高度免疫原性的，并且当IV（R. Seder等人，正在编写中）。Roestenberg及其同事（2）已独立证明，经氯喹治疗的志愿者通过蚊子叮咬给予非减毒NF 54 PfSPZ可获得高水平（100%）、持久（28个月）的保护，这种方法称为子孢子化学预防（CPS）。我们已经通过PfSPZ的ID给药成功感染了志愿者（称为PfSPZ激发）（3），最近通过IV给药3，200 PfSPZ（Mordmueller，准备中）感染了100%的志愿者（9/9）。PfSPZ攻毒的这些发现确立了将CPS快速转化为实用疫苗方法的方法，称为PfSPZ-CVac，其中PfSPZ攻毒与氯喹化学预防一起施用。PfSPZ-CVac的首次临床试验正在进行中。虽然有限的可用证据表明，整个PfSPZ免疫接种可以诱导对同源和异源CHMI攻击的保护，我们认为，由至少3个不同地理来源的Pf菌株组成的多价疫苗将最好地确保全球保护。我们在该项目中的目标是鉴定可用于以下的氯喹敏感性Pf菌株：1）在CHMI中评估基于PfSPZ的疫苗的广谱功效，以及2）如果有需要，将这些菌株作为多价疫苗组分包括在内以实现广泛功效。为了实现这一目标，我们将对来自非洲和亚洲的至少2种氯喹敏感的Pf菌株进行连续培养，这些菌株表现出适合Sanaria PfSPZ生产工艺的无性生长和有性阶段以及孢子生殖发育特征。在过去的30年中，只有少数寄生虫菌株已经建立，能够产生适当丰富的PfSPZ从培养的配子体。实现我们的目标将需要Sanaria独特的工业化PfSPZ生产方法，包括在Sanaria的研发设施中系统筛选多种氯喹敏感的寄生虫分离株，其中配子体培养，蚊子感染和PfSPZ提取和定量分析是连续进行的。使用异源Pf菌株测试异源保护效力和启动多价疫苗制造的能力可以将PfSPZ疫苗的上市时间缩短至少2年，节省数千万至数亿美元的成本。

DESCRIPTION (provided by applicant): The ideal tool for eliminating Plasmodium falciparum (Pf), the causative agent of 99% of all malaria deaths, is a highly effective vaccine that entirely prevents blood stage infection and thereby prevents all disease and transmission. Sanaria's goal is to develop and commercialize a Pf sporozoite (SPZ) vaccine that prevents Pf blood stage infection in > 80% of recipients. Sanaria developed a vaccine composed of attenuated, purified, aseptic, cryopreserved PfSPZ, the PfSPZ Vaccine based on the chloroquine-sensitive NF54 strain of Pf. It is safe and well-tolerated when administered to human volunteers by intradermal (ID), subcutaneous (SC) or intravenous (IV) injection (1). It is highly immunogenic and conferred high level protection (100%) against homologous controlled human malaria infection (CHMI) when administered IV (R. Seder et al., in prep.). Roestenberg and co-workers (2) have independently demonstrated high level (100%), long-lasting (28 months) protection with non-attenuated NF54 PfSPZ administered to chloroquine-treated volunteers by the bites of mosquitoes, an approach referred to as chemoprophylaxis with sporozoites (CPS). We have achieved successful infection of volunteers with ID administration of PfSPZ (called PfSPZ Challenge) (3), and recently infected 100% of volunteers (9/9) with IV administration of 3,200 PfSPZ (Mordmueller, in prep.). These findings with PfSPZ Challenge establish the means to rapidly translate CPS into a practical vaccine approach, termed PfSPZ-CVac, in which PfSPZ Challenge is administered with chloroquine chemoprophylaxis. The first clinical trial of PfSPZ-CVac is now in progress. While the limited available evidence suggests that whole PfSPZ immunization can induce protection against homologous and heterologous CHMI challenge, we assume that a multivalent vaccine composed of at least 3 Pf strains of diverse geographic origin will best insure worldwide protection. Our goal in this project is to identify chloroquine sensitiv strains of Pf that can be used: 1) in CHMI to assess the broad-spectrum efficacy of PfSPZ-based vaccines and 2) if there is a need, to include these strains as multivalent vaccine components to achieve broad efficacy. To accomplish this we will adapt to continuous culture at least 2 chloroquine sensitive strains of Pf from Africa and Asia that exhibit asexual growth and sexual stage and sporogonic development characteristics suitable for Sanaria's PfSPZ manufacturing process. During the past 30 yrs, only a few parasite strains have been established that are capable of producing suitably abundant PfSPZ from cultured gametocytes. Achieving our aims will require Sanaria's unique, industrialized approach to PfSPZ production, including systematic screening of multiple chloroquine sensitive parasite isolates in Sanaria's R&D facility where gametocyte culture, mosquito infection, and PfSPZ extraction and quantitative analysis is carried out continuously. The ability to test heterologous protective efficacy and initiate multivalent vaccine manufacturing using heterologous Pf strains could reduce the time to market for PfSPZ vaccines by at least 2 years, with cost savings of tens to hundreds of millions of dollars.